The present invention relates to a method for enhancing skin penetration of therapeutic agents utilizing certain 1,3-dioxacyclopentanes and 1,3-dioxacyclohexanes and compositions containing such compounds as well as to new penetration enhancing compounds within these chemical classifications.
The desirability, of the delivery of physiologically active agents through the skin, i.e. transdermally, as opposed to other methods of parenteral administration or via the digestive system is based on many factors. The large surface area of the skin (over 3,000 square inches for the average adult) and the large circulatory (about one-third of total body blood) and lymphatic networks available near the skin, the generally non-invasive nature of topical applications and their delivery through the skin, the convenience, the safety, the potential greater control of delivered agents, and the minimal side effects are just some of the advantages seen for this technique.
While not every and all agents may be suitable for transdermal delivery because of local irritation, allergic reactions, etc., most are indicated as suitable but, unfortunately, the greatest problem is overcoming the general barrier to drug penetration (or indeed to any material) of the skin. A drug must pass through the outer layer of skin or epidermis and into the dermis layer before being absorbed into the blood stream. The epidermis comprises two main parts, the stratum corneum and the stratum germinativum. The stratum corneum forms the outermost layer of the epidermis and consists of many stralified layers of compacted, flattened, keratinized cells which have lost their nuclei. This outmost layer serves as a physical barrier to light, heat, microorganisms and most chemical agents. In addition, it behaves as a primary barrier to percutaneous absorption. Because of the barrier effect of the skin, it has heretofore only been possible to deliver drugs that are "low-dose" drugs, in the range of 10 mg/day or less, or those of low molecular weight. In addition they have to have the proper lipophilic-hydrophilic balance to permit adequate absorption. It was recognized as early as the beginning of this century that lipid-soluble substances, such as nonelectrolytes have a comparatively greater skin permeability than water-soluble substances, such as electrolytes.
The phenomenon of percutaneous absorption or transdermal permeation can be viewed as a composite of a series of steps in sequence, that is, adsorption of a penetrant molecule onto the surface layers of stratum corneum, diffusion through it and through the viable epidermis, and finally through the papillary dermis and into the microcirculation. The great diffusional resistance of stratum corneum has been demonstrated in a comparative absorption of drugs, like hydrocortisone. The mucous membranes in the rectal and vaginal regions permit the absorption of 26-29% of the steroid applied, while less than 2% of the applied dose is absorbed through the skin.
Compounds which are known or reported to enhance the transdermal delivery of drugs include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, alkyl lactams, and long-chain amides. Prior art patents of relevance to penetrating enhancers for physiologically active agents include U.S. Pat. Nos. 3,551,554 which describes dimethyl sulfoxide; 3,989,816 discloses 1-substituted azacycloheptane-2-one; U.S. Pat. No. 4,132,781 discloses a topical antibiotic plus 2-pyrrolidone or an n-lower alkyl-2-pyrrolidone, U.S. Pat. No. 4,017,641 also describes 2-pyrrolidone but with propylene glycol; others of interest are U.S. Pat. Nos. 3,903,256; 4,343,798; 4,046,886; 3,934,013; 4,070,462; 4,130,643; 4,130,667; 4,289,764; 4,070,462; 3,527,864; 3,535,422, 3,598,123, 3,952,099, 4,379,454, 4,286,592; 4,299,826; 4,314,557; 4,343,798; 4,335,115; 3,598,122; 4,405,616, 3,896,238 and 3,472,931. Attention is also directed to U.S. Pat. No. 4,557,934 and this patent as well as the others previously mentioned are hereby incorporated in their entirety by reference thereto. None of the references cited heretofore discloses any 1,3 dioxolane or 1,3 dioxane and especially any of the substituted types previously mentioned and hereinafter described for use as percutaneous absorption enhancers for physiologically active substances.